Chronic kidney disease (CKD) often leads to irreversible deterioration of renal function that often progresses to End Stage Kidney Disease (ESKD). CKD has emerged as a serious public health issue and data obtained from the USRDS reveals that the number of new cases of ESKD in the United States is projected to exceed 700,00 patients by year 2015. As glomerular diseases secondary to podocyte dysfunction contribute up to 80% of all ESKD, a detailed molecular and genetic approach to identify mechanisms for podocyte development and repair may give us new targets for developing therapeutic agents. Recent cell culture models have described the possible role of endocytosis in podocytes. To further determine its importance, we identified important genes regulating endocytosis, synaptojanin 1, and dynamin, which when deleted in mice results in severe proteinuria and foot process effacement. We also identified endophilin, an interactor of synaptojanin 1 and dynamin through a proteomic screen, and loss of endophilin also results in severe proteinuria. Interestingly, other proteins such as CD2AP and Myo1e, which are central to the integrity of foot processes via genetic studies in humans are dynamin and synaptojanin 1 interactors. In Aim 1, we will define the fundamental mechanisms on how loss of endocytic regulation contributes to podocyte dysfunction. In Aim 2, we will characterize the role of endophilin in glomerular biology, and investigate the link between endocytosis and actin in podocytes. Lastly, in Aim 3, we will incorporate mice glomerular injury models to identify the impact of endocytosis after injury. Our results strongly implicate a protein network that controls clathrin-mediated endocytosis in the formation and maintenance of the glomerular filtration barrier. By completing these aims, we will have an opportunity to further expand our knowledge of endocytic pathways vital for podocyte homeostasis. PUBLIC HEALTH RELEVANCE: Kidney injury that results in inflammation and urinary protein loss often progress to irreparable damage where patients require a kidney transplantation or dialysis to survive. In the United States, the number of new cases of chronic kidney disease is expected to exceed 700,000 by year 2015 and the majorities are due to damage to the kidney's filtration barrier. Hence, the goal of this proposal is to unravel the fundamental mechanisms and pathogenesis of this disease process so that in the near future new therapeutic options are available.